Bruton's Tyrosine Kinase (BTK) is a member of the tyrosine kinase TEC family and plays an important role in B cell activation and cell transduction. B cell receptor (BCR) is a key regulatory site for B cell activity, abnormal signaling can cause dysregulated B cell proliferation and the formation of pathogenic autoantibodies, leading to a variety of autoimmune diseases and inflammatory diseases.
BTK is located at the membrane-proximal section and immediately downstream of BCR, BTK deficiency can block BCR signaling. Thus, an effective therapeutic approach to block B cell mediated diseases can be provided by inhibiting BTK. BTK inhibitors can be used in the treatment of diseases such as rheumatoid arthritis, B cell lymphoma, leukemia, multiple myeloma, allergies, asthma, multiple sclerosis, type I diabetes and systemic lupus erythematosus. Currently, two BTK inhibitors being developed extensively are ibrutinib and ACP-196 (acalabrutinib). The former was approved by FDA in 2013 for the treatment of mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). The latter is currently in phase III clinical trials.
Both BTK inhibitors have some toxic side effects, such as: thrombocytopenia, decreased hemoglobin, diarrhea, neutropenia, anemia, fatigue, headache, musculoskeletal pain, angioedema, upper respiratory tract infection, nausea, bruising, dyspnea, constipation, rash, arthralgia, bellyache, vomiting and loss of appetite etc. In the two inhibitors, the toxic side effects of ibrutinib are much larger than those of ACP-196 (Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia (The New England Journal of Medicine, 374; 4, 2016)).
These toxic side effects are caused by the low selectivities to the kinase and the long half lives of the drugs.
In literature: Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia (The New England Journal of Medicine, 374; 4, 2016), it is disclosed that three kinases, EGFR/ITK/TEC are clearly related to side effects.
In a conference paper: Presented at the 2nd International Conference on New Concepts in B-cell Malignancies; 9-11 Sep. 2016; Estoril, Portugal, it is disclosed that the half life of ibrutinib was 6 hours and the half life of ACP-196 was 1.13 hours.